Blog Archive

Monday, 2 June 2008

Weekly BioNews 26 - 03 May - Jun 2008

Researchers at The University of Nottingham have taken some important first steps to creating a synthetic copycat of a living cell, a leading science journal reports.

Dr Cameron Alexander and PhD student George Pasparakis in the University's School of Pharmacy have used polymers — long-chain molecules — to construct capsule-like structures that have properties mimicking the surfaces of a real cell.

In work published as a 'VIP paper' in the journal Angewandte Chemie International Edition, they show how in the laboratory they have been able to encourage the capsules to 'talk' to natural bacteria cells and transfer molecular information.

The breakthrough could have a number of potential medical uses. Among them could be the development of new targeted drug delivery systems, where the capsules would be used to carry drug molecules to attack specific diseased cells in the body, while leaving healthy cells intact, thereby reducing the number of side affects that can be associated with treatments for life-threatening illnesses such as cancer.

The technology could also be used as an anti-microbial agent, allowing doctors to destroy harmful bacteria, without attacking other health-promoting bacteria in the body, which could offer a new weapon in the fight against superbugs....

A monkey has successfully fed itself with fluid, well-controlled movements of a human-like robotic arm by using only signals from its brain, researchers from the University of Pittsburgh School of Medicine report in the journal Nature. This significant advance could benefit development of prosthetics for people with spinal cord injuries and those with “locked-in” conditions such as Lou Gehrig’s disease, or amyotrophic lateral sclerosis.

“Our immediate goal is to make a prosthetic device for people with total paralysis,” said Andrew Schwartz, Ph.D., senior author and professor of neurobiology at the University of Pittsburgh School of Medicine. “Ultimately, our goal is to better understand brain complexity.”

Previously, work has focused on using brain-machine interfaces to control cursor movements displayed on a computer screen. Monkeys in the Schwartz lab have been trained to command cursor movements with the power of their thoughts.

“Now we are beginning to understand how the brain works using brain-machine interface technology,” said Dr. Schwartz. “The more we understand about the brain, the better we’ll be able to treat a wide range of brain disorders, everything from Parkinson’s disease and paralysis to, eventually, Alzheimer’s disease and perhaps even mental illness.”

Using this technology, monkeys in the Schwartz lab are able to move a robotic arm to feed themselves marshmallows and chunks of fruit while their own arms are restrained. Computer software interprets signals picked up by probes the width of a human hair. The probes are inserted into neuronal pathways in the monkey’s motor cortex, a brain region where voluntary movement originates as electrical impulses. The neurons’ collective activity is then evaluated using software programmed with a mathematic algorithm and then sent to the arm, which carries out the actions the monkey intended to perform with its own limb. Movements are fluid and natural, and evidence shows that the monkeys come to regard the robotic device as part of their own bodies.

In Germany alone, about three million – mostly elderly – patients suffer from poorly healing large-area wounds caused by complaints such as diabetes, burns or bedsores. The wounds can be treated with conventional collagen dressings or polylactic acid dressings, but the success rate is not as good as it should be.

A new type of dressing made of silica gel fibers, developed by scientists at the Fraunhofer Institute for Silicate Research ISC in Wurzburg, shall solve the problem. This novel dressing has many advantages: it is shape-stable, pH-neutral and 100 percent bioresorbable. Once applied it remains in the body, where it gradually degrades without leaving any residues. What’s more, the fibre fleece provides the healthy cells around the edges of the wound with the structure they additionally need for a proper supply of growth-supporting nutrients. To prevent any infection, treatment of the wound must be absolutely sterile. “As only the outer bandage needs to be changed, the risk of contaminating the wound is low,” explains Dr. Jorn Probst of the ISC. And thanks to the supporting matrix for the cells, the chances of a scar-free natural closure of the wound are very good.

The fibers are produced by means of wet-chemical material synthesis, a sol-gel process in which a transparent, honey-like gel is produced from tetraethoxysilane (TEOS), ethanol and water in a multi-stage, acidically catalyzed synthesis process. The gel is processed in a spinning tower: “We press it through fine nozzles at constant temperatures and humidity levels,” explains Walther Glaubitt, the inventor of the silica gel fibers. “This produces fine endless threads which are collected on a traversing table and spun in a specific pattern to produce a roughly A4-sized multi-layer textile web.” The dressings are then cut, packed and sterilized. Dr. Jorn Probst and Dipl.-Ing. Walther Glaubitt will receive the Joseph von Fraunhofer Prize 2008 for developing the biocompatible dressing.....

According to some experts, newly born neuronal stem cells in the adult brain may provide a therapy for brain injury. But if these stem cells are to be utilized in this way, the process by which they are created, neurogenesis, must be regulated.

A new study, led by Laurence Katz, Co-Director of the Carolina Resuscitation Research Group at the University of the North Carolina School of Medicine, suggests a way in which this might be achieved.

According to the research, neurogenesis can be regulated through induced hypothermia. In rat subjects, a mild decrease in body temperature was found to substantially decrease the proliferation of newly-born neurons, a discovery that marks a major step forward for the development of neuronal stem cell-based brain therapies.

Since the 1930s, brain damage from stroke, head injury, near drowning and cardiac arrest was considered to be permanent because of a lack of repair mechanisms like other parts of the body. However, discovery of neuronal stem cells in the adult brain challenges that belief.

“Many questions remain before we adequately understand how to control these cells to repair a damaged brain,” says Katz. “However, the findings represent an important step in demonstrating that these cells can be controlled by simple external forces like hypothermia.....

- Sticky Business: Researchers Devise New Way Of Mapping The Viscosity Of Cells

ScienceDaily (May 30, 2008)

A fluorescent dye can be used to map how viscous, or 'gloopy', different parts of a cell are, according to new research published in the Journal of the American Chemical Society.

Changes in viscosity have been linked to disease and malfunction in human cells. For example, changes in the viscosity of the membranes of red blood cells have been observed in diabetes patients. Knowing more about these changes could lead to a greater understanding of how some diseases affect the human body.

Now a team of scientists from Imperial in collaboration with Kings College London has demonstrated that a fluorescent dye can be used to show how viscous different parts of a cell are, compared to one another.

The dye is made of a molecule which has a component that can freely rotate or naturally spin, like a molecular rotor. The researchers demonstrated that the speed of rotation of this molecule can be used to monitor local viscosity.

One of the lead authors on the paper, Dr Gokhan Yahioglu from Imperial's Department of Chemistry and the Imperial spin-out company PhotoBiotics Ltd explains: "We have taken a molecule often used as a fluorescent marker in cells and used it as a true molecular rotor where the intensity and duration of the molecule's fluorescence is strongly linked to the viscosity of the cell into which it is introduced. This means we have developed a sensitive and versatile method for measuring the local micro-viscosity in biological systems....

The flourescent dye is used to map viscosity in human ovarian cancer cells. (Credit: Image courtesy of Imperial College London)

Scientists have looked at the problem of understanding the regulatory mechanisms that create different cells from a single template by using the olfactory system of the fruit fly. The ability to discriminate odors depends on receptor cells expressing different patterns of receptor genes, despite each cell having the same genes. Receptor patterns are controlled by DNA sequences upstream of the receptor genes.

It may appear difficult to reconcile the fact that almost every cell in the body of an animal has an identical dose of genes with the variety of different appearances and properties cells can display--bone, skin, hair, muscle, and many more. This may seem even more complex given that all of these tissue types derive originally from a single fertilized egg cell. Understanding the many regulatory mechanisms that create different cells from a single template is the work of developmental biology.

A new paper looks at this problem in the olfactory system of the fruit fly, where the ability to discriminate odors depends on receptor cells expressing different patterns of receptor genes, despite each cell having the same set of genes to choose from. The paper, by Anandasankar Ray and colleagues at Yale University, shows that receptor patterns are controlled by DNA sequences upstream of the receptor genes.

In the fruit fly Drosophila, there are two organs involved in smell: the antennae and the maxillary palps--the latter being part of the mouth. In these palps, there are always six types of neurons, cells that transmit information from the sensing part to the brain. Each type of neuron has a different, predictable pattern of olfactory receptors. How a neuron knows which receptors to express was, until now, a mystery.....

A Weizmann Institute study provides important new insights into the process of viral infection. The study, reported in the online journal PLoS Biology, reveals certain mechanisms by which mimivirus – a virus so called because it was originally thought to mimic bacteria in various aspects of their behavior – invades amoeba cells.

Living cells become infected by viruses in two steps. First, the virus penetrates the cell. Next, in the second and crucial step, the cell starts producing new viruses, which spread and infect additional cells. At the beginning of this production process, the cell makes the outer wall of the virus, which is a container of sorts composed of proteins and known as the capsid. The cell then makes copies of viral DNA and inserts it into the capsid. The result is a new, functioning virus that is ready to leave the host cell and infect more cells.

Understanding how viruses infect cells and how new viruses are produced in the course of the infection allows scientists to interrupt the infection cycle, blocking viral diseases. One of the difficulties, however, is that the invasion strategies of different viruses greatly vary from one another.

The mimivirus, known, among other things, for its exceptional size – it is five to ten times larger than any other known virus – poses an interesting challenge in this respect. This virus was discovered only in the late twentieth century, as its extraordinary size made it impossible to identify it by regular means. In addition, it contains much more genetic material than other viruses, a feature that forces the mimivirus to develop particularly efficient methods for introducing its viral DNA into the host cell and for inserting the genetic “parcel” into the protein container during the production of new viruses in the host cell....

Researchers at the University of Pennsylvania School of Medicine have shown how Argos, a fruit fly protein, acts as a 'decoy' receptor, binding growth factors that promote the progression of cancer. Knowing how Argos neutralizes tumor growth may lead to new drug designs for inhibiting cancer. The study appeared online in Nature in advance of print publication.

Many types of tumors grow because of over-expression of a protein known as the epidermal growth factor receptor (EGFR) or a peptide hormone called epidermal growth factor (EGF) that binds and activates EGFR. Argos mimics EGFR by binding to EGF. But, unlike EGFR, Argos does not signal cells to grow.

In theory, surmise the researchers, a drug designed to resemble Argos could bind cancer growth factors and prevent them from signaling cancer cell growth. The investigators previously found that Argos works this way in the fruit fly, binding and neutralizing the fly version of EGF called Spitz. Inhibition of Spitz in this way is crucial for proper development of the fly eye.

"There are several 'designer' cancer drugs that fight tumors driven by EGFR-like receptors, such as Herceptin, Erbitux and Tarceva," says lead author Mark A. Lemmon, PhD, Professor of Biochemistry and Biophysics. "Whereas these drugs all attack the receptor itself, an Argos-like drug would instead neutralize the cancer growth factor by mimicking a silent receptor. This is a change in paradigm for tumor-growth inhibition in this class of cancers."

Approaches using molecules that neutralize growth factors have proven themselves in other cases. The Avastin antibody works well to block the molecule that activates the vascular endothelial growth factor receptor and several drugs can block tumor necrosis factor-α in arthritis, including Remicade, Humira and Enbrel. An Argos-like drug would work the same way in EGFR signaling, suggests Lemmon....

University of Texas Medical Branch at Galveston researchers have developed new vaccines to protect against West Nile and Japanese encephalitis viruses. The investigators created the vaccines using an innovative technique that they believe could also enable the development of new vaccines against other diseases, such as yellow fever and dengue fever, which are caused by similar viruses.The scientists showed that the vaccines successfully protected laboratory mice and hamsters against the viruses, which can cause fatal brain inflammation in humans. They reported their findings in back-to-back papers published in the current issue of the journal Vaccine.

"These vaccines were created using a system that we think is applicable to producing vaccines that can protect against a wide range of diseases caused by the flaviviruses, an important family of viruses that afflict populations throughout the world," said UTMB pathology professor Peter Mason, senior author of the Vaccine papers. "Flaviviruses cause tremendous human suffering, but we still only have vaccines for a few of them."

Currently approved flavivirus vaccines are either "live-attenuated virus" vaccines, which contain weakened but still genetically intact versions of the target virus, or "inactivated-virus" vaccines, which contain viruses that have been chemically neutralised. In each case, the viral material stimulates the immune system to block the progress of any future infection by the virus in question.

The new vaccines - based on a concept devised by Mason and UTMB microbiology and immunology associate professor Ilya Frolov - are known as "single-cycle" or "pseudoinfectious" vaccines, and contain flaviviruses that have been genetically modified so that each virus can only infect a single cell. Unable to spread from cell to cell and create disease, these crippled viruses nonetheless continue to copy themselves within the cells they infect, thus producing the viral proteins needed to induce immune protection.

"With these vaccines, we mimic a viral infection and get amplification of the antigens that are important for stimulating an immune response without amplification of the virus," Mason said....

Mayo Clinic researchers have developed an animal model that can test the function of two prominent tumor suppressor genes, p16 and p19, in the aging process. Scientists knew that both these genes were expressed at increased levels as humans and mice age, but their role in the ageing process was not clear. Findings by the Mayo team show that p16 provides gas to accelerate cellular ageing, while p19 stops that process.The findings, to be published May 30 in the online issue of Nature Cell Biology, could help explain the development of some characteristics associated with ageing, such as loss of muscle mass and strength or cataracts, and how they might be retarded.

"Scientists interested in ageing have developed mice that lack p16 or p19, but these mice were not suitable for studies on ageing because they all die of cancer before they even begin to age," says the study's first author, Darren Baker, a laboratory technician at Mayo Clinic and a doctoral candidate. "By crossing these mice with a mouse strain that ages five times faster than normal due to a mutation in the BubR1 gene, we were able to bypass this problem."

While other genes are involved in ageing, the researchers firmly established that when too much p16 is produced, tissues start to age. Instead of driving ageing, the p19 gene was found to counteract the effects of p16. This was completely unexpected, says Jan van Deursen, Ph.D., a molecular biologist at Mayo Clinic, because tissue culture experiments had predicted that p19 expression promotes ageing....

Uncontrolled reaction of organic compounds with oxygen is easy: we call it fire. But nature often needs to do oxidations very specifically, adding oxygen to a particular carbon atom in a complicated molecule without disturbing anything else. Usually, this job falls to an enzyme called cytochrome P450. Because cytochrome P450 can catalyse molecular oxidations with pinpoint accuracy, it has been called "nature's blowtorch," and its job is analogous to that of a welder doing a tricky repair in a highly flammable wooden house. It needs to do the repair without burning itself or the house.Brandeis University researchers have been trying to understand the details of how P450 does this job so efficiently; that is, "burning" the right places in the target molecule (substrate) while not "burning down the house."

In new research online in the Cell Press journal Structure, chemistry graduate student Bo OuYang, along with fellow grad student Marina Dang and advisors Thomas and Susan Pochapsky, describe a new insight into how P450 works. The researchers discovered that the protein chain in P450 can change its structure by a 180 degree rotation around a single peptide bond. In one orientation, both oxygen and the molecule to be oxidised (substrate) can get in and out of the P450 active site, but the oxygen is not "activated," that is, it is not in a state to react with the substrate (or anything else, for that matter).

In the other orientation, however, the substrate is held tightly in the correct orientation for the oxidation, and the oxygen can be activated to do "the burn." The activated form of the molecule is generated by binding a helper protein, called Pdx, to the P450. This binding drives the reorientation around the peptide bond, and moves the P450 from the form in which substrate binds to the active form. After the reaction is finished, the Pdx falls off, the P450 moves back to the unactivated state, and the oxidised products are free to leave...